The pro-inflammatory cytokine IL-17 has been implicated in joint destruction and in the inflammatory pathogenesis of rheumatoid arthritis (RA) in human studies. Targeted deletion or inhibition of IL-17 leads to significant reduction in disease severity in animal models of RA. A recently discovered lineage of CD4+ T cells, functionally distinct from the better known CD4+ T helper cells Th1 and Th2, expresses IL-17 and is referred to as Th-17. IL-23 is a survival factor for Th-17 cells. Since IL-23 knockout animals are resistant to induction of RA, Th-17 cells are potentially of major importance in the pathogenesis of the disease. The applicants have identified small molecule ligands to an orphan receptor that is required for the formation of Th-17 cells and have shown that receptor antagonists block Th-17 differentiation from na[unreadable]ve CD4+ T cells. In this study, we propose to evaluate the utility of this novel receptor as a drug target for RA by identifying lead compounds with good pharmacokinetic properties for testing in murine collagen-induced arthritis (CIA), an established animal model of RA. Current receptor antagonists are not suitable for definitive in vivo studies. The specific aims of this investigation will include: (1) synthesis of analogs to promising drug-like hits with a medicinal chemistry partner in order to increase potency and improve metabolic stability for in vivo testing; (2) identification of the major IL-17+ T cell types induced in CIA draining lymph nodes and characterization of their response to receptor ligands; and (3) evaluation of lead compound effects in CIA both during disease induction and from the time of first symptoms, about day 30, in order to better understand the mechanism of drug effect. The toxicity and secondary immune effects of this new compound class will be investigated as well. Our goal is to create an entirely new class of orally-bioavailable drugs for RA that blocks the major T cell-mediated arm of immune pathogenesis in the disease, thereby providing an efficacious therapy with reduced side effects and broader therapeutic utility in comparison to steroids, methotrexate and other small molecule drugs routinely used for treatment of RA. With regard to relevance to public health, rheumatoid arthritis (RA) is a painful and crippling disease that affects two million Americans. New drugs that target the immune system (such as entanercept and infliximab) have provided relief for some but not all patients, but the drugs also have serious side effects that may limit their use. The proposed studies would take the first step to develop a new class of small molecule, orally-bioavailable drugs designed to inhibit the function of a novel, potentially pathogenic immune cell that recent scientific evidence strongly suggests is involved in the pathogenesis of RA. [unreadable] [unreadable] [unreadable]